Pharmacotherapy for smoking cessation is universally accepted as standard of care and is highly cost effective, although only approximately 20% who attempt cessation are successful on a given attempt and up to 90% of those who do quit relapse to smoking within one year, and most relapse within two weeks of quitting. Discovery of novel treatments to aid people who want to quit smoking for the long term is a clear public health priority. People smoke for rewarding effects of nicotine, but also to avoid withdrawal-emergent symptoms such as cognitive impairment. Nicotine withdrawal is associated with significant attentional impairment, a symptom that is strongly associated with relapse to smoking. Those with baseline cognitive impairment are also more likely to smoke and less likely to quit than those without such symptoms. In many cases, nicotine ameliorates baseline cognitive symptoms. This R-01 grant application is based on the hypothesis that pharmacotherapies that work through novel biological mechanisms to moderate baseline and withdrawal-emergent symptoms such as cognitive impairment hold the greatest promise for sustained abstinence. We propose to evaluate the effect of a novel, selective, oral, alpha-7 nicotinic acetylcholine receptor agonist, EVP 6124, that is in Phase II development with an active IND, and has been shown to improve cognitive performance in normal adults, and those with schizophrenia and dementia of the Alzheimer's type. To do so, we propose to conduct a Phase II, double-blind, proof of concept treatment trial, comprising 4 combinations of active treatment and placebo arms in a 2 by 2 factorial design (EVP 6124 plus NRT vs placebo plus NRT vs EVP 6124 plus placebo-NRT vs placebo plus placebo-NRT). All participants will attempt to quit smoking on study day 1 when study medications are initiated. NRT or placebo-NRT (active or placebo patch) will be continued for 6 weeks and then discontinued. Randomized oral medication will then be continued without NRT for an additional 6 weeks in a relapse prevention phase. Participants will be followed for relapse patterns for 2 weeks after oral treatment discontinuation, to week 14. Data on cognitive performance, smoking behavior, and tolerability will be collected at each weekly visit. This design will allow us to assess the assay sensitivity of the clinical trial itself (by comparing the placebo plus NRT arm with the placebo plus placebo-NRT arm) and to assess whether the selective alpha-7 nicotinic receptor agonist is effective as monotherapy (by comparing the EVP 6124 plus placebo-NRT arm with the placebo plus placebo-NRT arm) and/or in combination with NRT (by comparing EVP 6124 plus NRT arm with the placebo plus NRT arm). In so doing, we will discover if the selective alpha-7 nAChR agonist improves cognitive performance during nicotine taper and in early abstinence and if this effect is associated, compared to placebo, with greater sustained abstinence from tobacco smoking alone or in combination with NRT. PUBLIC HEALTH RELEVANCE: One in five Americans smoke tobacco. Each year over 430,000 people in the US and 5 million worldwide die from smoking-related illness, and the global mortality toll is rising. Clearly, more effective pharmacotherapies are urgently needed. In this study, we aim to discover whether a novel treatment will work alone or in combination with nicotine replacement to aid cessation and reduce relapse by minimizing nicotine withdrawal- induced cognitive impairment